The use of oligonucleotide probes to modulate the synthesis of protein molecules has had important implications in understanding the growth of viruses and expression of oncogenes. More recently, antisense strategies have been employed in studies examining the nervous system. The applications of this methodology are numerous. Essentially, this technique represents a "knock-out" method by which the endogenous role of particular proteins.can be examined by both in vitro and in vivo investigations. We will develop this technology by designing oligonucleotide probes to the serotonin2 (5-HT2) receptor which represents a good model in which to define the parameters needed to achieve functional knockout. The system will be modelled in vitro using homogenous cell cultures expressing the rat 5-HT2 receptor. Subsequently, effective antisense probes will be administered to whole animals to determine behavioral and biochemical consequences of 5-HT2 receptor inactivation. The ultimate goal of this approach is to apply the technology to proprietory receptor sites to enable direction of conventional small molecule drug development by identifying potential therapeutic targets.